Breaking boundaries in diabetic nephropathy treatment: design and synthesis of novel steroidal SGLT2 inhibitors†

Abstract

The activity of sodium glucose co-transporter 2 (SGLT2) has always been an important parameter influencing chronic kidney disease in type-2 diabetic patients. Herein, we have meticulously designed, synthesized, and evaluated several novel steroidal pyrimidine molecules that possess the capability to successfully bind to the SGLT2 protein and inhibit its activity, thereby remedying kidney-related ailments in diabetic patients. The lead steroidal pyrimidine compounds were selected after virtually screening from a library of probable N-heterocyclic steroidal scaffolds. A nano-catalyzed synthetic route was also explored for the synthesis of the steroidal pyrimidine analogs demonstrating an environmentally benign protocol. Extensive in vitro investigations encompassing SGLT2 screening assays and cell viability assessments were conducted on the synthesized compounds. Among the steroidal pyrimidine derivatives evaluated, compound 9a exhibited the highest SGLT2 inhibition activity and underwent further scrutiny. Western blot analysis was employed to determine the impact of 9a on inflammatory and fibrotic proteins, aiming to elucidate its mechanism of action. Additionally, in silico analyses were performed to illuminate the structural dynamics and molecular interaction mechanism of 9a. The overall investigation is crucial for advancing the development of the next generation of anti-diabetic drugs.